Macrocyclic heterocyclic aspartyl protease inhibitors

ABSTRACT

Disclosed are compounds of the formula I 
                         
or a stereoisomer, tautomer, or pharmaceutically acceptable salt, solvate or ester thereof, wherein U, W, X, L, Y, M, Z, c, d, e, f, g, h, s, t, R 1 , R 2 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17  and R 18  are as defined in the specification; and pharmaceutical compositions comprising the compounds of formula I.
 
     Also disclosed is the method of inhibiting aspartyl protease, and in particular, the methods of treating cardiovascular diseases, cognitive and neurodegenerative diseases. Also disclosed are methods of treating cognitive or neurodegenerative diseases using the compounds of formula I in combination with a cholinesterase inhibitor or a muscarinic m 1  agonist or m 2  antagonist.

CROSS REFERENCE TO RELATED APPLICATIONS

This application claims the benefit of U.S. Provisional Application No.60/690,542 filed on Jun. 14, 2005.

FIELD OF THE INVENTION

This invention relates to macrocyclic heterocyclic aspartyl proteaseinhibitors, pharmaceutical compositions comprising said compounds, theiruse in the treatment of cardiovascular diseases, cognitive andneurodegenerative diseases, and their use as inhibitors of the HumanImmunodeficiency Virus, plasmepsins, cathepsin D and protozoal enzymes.

BACKGROUND

Human aspartic proteases of the A1 (pepsin-like) family are as follows:pepsin A and C, renin, BACE, BACE 2, Napsin A, cathepsin D inpathological conditions.

The role of renin-angiotensin system (RAS) in regulation of bloodpressure and fluid electrolyte has been well established (Oparil, S, etal. N Engl J Med 1974; 291:381-401/446-57). The octapeptideAngiotensin-II, a potent vasoconstrictor and stimulator for release ofadrenal aldosterone, was processed from the precursor decapeptideAngiotensin-I, which in turn is processed from angiotensinogen by therenin enzyme. Angiotensin-II is also found to play roles in vascularsmooth muscle cell growth, inflammation, reactive oxygen speciesgeneration and thrombosis and influence atherogenesis and vasculardamage. Clinically, the benefit of interruption of the generation ofangiotensin-II through antagonism of conversion of angiotensin-I hasbeen well known and there are a number of ACE inhibitor drugs on themarket. The blockade of the earlier conversion of angiotensinogen toangiotensin-I, i.e. the inhibition of renin enzyme, is expected to havesimilar but not identical effects. Since renin is an aspartyl proteasewhose only natural substrate is angiotensinogen, it is believed thatthere would be less frequent adverse effect for controlling high bloodpressure and related symptoms regulated by angiotensin-II through itsinhibition.

Another protease, Cathepsin-D, is involved in lysosomal biogenesis andprotein targeting, and may also be involved in antigen processing andpresentation of peptide fragments. It has been linked to numerousdiseases including, Alzheimer's, Disease, connective tissue disease,muscular dystrophy and breast cancer.

Alzheimer's Disease (AD) is a progressive neurodegenerative disease thatis ultimately fatal. Disease progression is associated with gradual lossof cognitive function related to memory, reasoning, orientation andjudgment. Behavioral changes including confusion, depression andaggression also manifest as the disease progresses. The cognitive andbehavioral dysfunction is believed to result from altered neuronalfunction and neuronal loss in the hippocampus and cerebral cortex. Thecurrently available AD treatments are palliative, and while theyameliorate the cognitive and behavioral disorders, they do not preventdisease progression. Therefore there is an unmet medical need for ADtreatments that halt disease progression.

Pathological hallmarks of AD are the deposition of extracellularβ-amyloid (Aβ) plaques and intracellular neurofibrillary tanglescomprised of abnormally phosphorylated protein tau. Individuals with ADexhibit characteristic Aβ deposits, in brain regions known to beimportant for memory and cognition. It is believed that Aβ is thefundamental causative agent of neuronal cell loss and dysfunction whichis associated with cognitive and behavioral decline. Amyloid plaquesconsist predominantly of Aβ peptides comprised of 40-42 amino acidresidues, which are derived from processing of amyloid precursor protein(APP). APP is processed by multiple distinct protease activities. Aβpeptides result from the cleavage of APP by β-secretase at the positioncorresponding to the N-terminus of Aβ, and at the C-terminus byγ-secretase activity. APP is also cleaved by α-secretase activityresulting in the secreted, non-amyloidogenic fragment known as solubleAPP.

An aspartyl protease known as BACE-1 has been identified as theβ-secretase activity responsible for cleavage of APP at the positioncorresponding to the N-terminus of Aβ peptides.

Accumulated biochemical and genetic evidence supports a central role ofAβ in the etiology of AD. For example, Aβ has been shown to be toxic toneuronal cells in vitro and when injected into rodent brains.Furthermore inherited forms of early-onset AD are known in whichwell-defined mutations of APP or the presenilins are present. Thesemutations enhance the production of Aβ and are considered causative ofAD.

Since Aβ peptides are formed as a result of β-secretase activity,inhibition of BACE-1 should inhibit formation of Aβ peptides. Thusinhibition of BACE-1 is a therapeutic approach to the treatment of ADand other cognitive and neurodegenerative diseases caused by Aβ plaquedeposition.

Human immunodeficiency virus (HIV), is the causative agent of acquiredimmune deficiency syndrome (AIDS). It has been clinically demonstratedthat compounds such as indinavir, ritonavir and saquinavir which areinhibitors of the HIV aspartyl protease result in lowering of viralload. As such, the compounds described herein would be expected to beuseful for the treatment of AIDS. Traditionally, a major target forresearchers has been HIV-1 protease, an aspartyl protease related torenin.

In addition, Human T-cell leukemia virus type I (HTLV-I) is a humanretrovirus that has been clinically associated with adult T-cellleukemia and other chronic diseases. Like other retroviruses, HTLV-Irequires an aspartyl protease to process viral precursor proteins, whichproduce mature virions. This makes the protease an attractive target forinhibitor design. (Moore, et al. Purification of HTLV-I Protease andSynthesis of Inhibitors for the treatment of HTLV-I Infection 55^(th)Southeast Regional Meeting of the American Chemical Society, Atlanta,Ga., US Nov. 16-19, 2003 (2003), 1073. CODEN; 69EUCH Conference, AN2004:137641 CAPLUS).

Plasmepsins are essential aspartyl protease enzymes of the malarialparasite. Compounds for the inhibition of aspartyl proteasesplasmepsins, particularly I, II, IV and HAP, are in development for thetreatment of malaria. (Freire, et al. WO 2002074719. Na Byoung-Kuk, etal., Aspartic proteases of Plasmodium vivax are highly conserved in wildisolates, Korean Journal of Parasitology (2004 June), 42(2) 61-6.Journal code: 9435800) Furthermore, compounds used to target aspartylproteases plasmepsins (e.g. I, II, IV and HAP), have been used to killmalarial parasites, thus treating patients thus afflicted.

Compounds that act as aspartyl protease inhibitors are described, forexample, in application U.S. Ser. No. 11/010,772, filed on Dec. 13,2004, herein incorporated by reference.

SUMMARY OF THE INVENTION

The present invention relates to compounds having the structural formulaI

or a stereoisomer, tautomer, or pharmaceutically acceptable salt,solvate or ester thereof, wherein

W is a bond, —C(═S)(C(R³)(R⁴))_(a)—, —(C(R³)(R⁴))_(a)C(═S)—,—S(O)₁₋₂(C(R³)(R⁴))_(a)—, —(C(R³)(R⁴))_(a)S(O)₁₋₂—,—C(═O)(C(R³)(R⁴))_(a)—, —(C(R³)(R⁴))_(a)C(═O)—, —O(C(R³)(R⁴))_(a)—,(C(R³)(R⁴))_(a)O—, —(C(R³)(R⁴))_(a)—, —N(R⁵)(C(R³)(R⁴))_(a)—,—(C(R³)(R⁴))_(a)N(R⁵)— or —C(═N(R⁵))(C(R³)(R⁴))_(a)—,—(C(R³)(R⁴))_(a)C(═N(R⁵))—; wherein a is 0-2;

U is a bond, —S(O)₁₋₂—, —C(═O)—, —O—, —P(O)(OR⁶)—, —(C(R³)(R⁴))_(b)—,—N(R⁵)— or —C(═N(R⁵))—; wherein b is 0-2; provided that when W is—S(O)—, —S(O)₂—, —O—, or —N(R⁵)—, U is not —S(O)—, —S(O)₂—, —O—, or—N(R⁵)—;

R¹ and R⁵ are independently selected from the group consisting of H,alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl,heterocycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl,arylcycloalkyl, —OR¹⁹, —CN, —C(O)R²⁰, —C(O)OR¹⁹, —S(O)₁₋₂R²¹,—C(O)N(R²²)(R²³), —S(O)₁₋₂N(R²²)(R²³), —NO₂, —N═C(R)(R²³) and—N(R²²)(R²³); or

R⁵ is

wherein R²⁶ numbers 0 to 5 substituents, m is 0 to 6 and n is 1 to 5;

R², R³, R⁴, R⁶, R⁷, R⁸, R⁹, R¹⁰, R¹¹, R¹², R¹³, R¹⁴, R¹⁵, R¹⁶, R¹⁷ andR¹⁸ are independently selected from the group consisting of H, alkyl,alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl,heterocycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl,arylcycloalkyl, halo, —CF₃, —SH, —OR¹⁹, —CN, —C(O)R²⁰, —C(O)OR¹⁹,—S(O)₀₋₂R²¹, —S(O)₁₋₂N(R²²)(R²³), —C(O)N(R²²)(R²³), —N(R²²)C(O)R²⁰,—N(R²²)C(O)N(R²²)(R²³), —N(R²²)C(O)OR¹⁹, —N(R²²)S(O)₁₋₂R²¹, —NO₂,—N═C(R²²)(R²³) and —N(R²²)(R²³); wherein c, d, e, f, g and h are 0-4;

X, Y and Z are independently selected from the group consisting of —O—,—N(R⁵)—, —C(O)—, —S(O)₀₋₂—, —C(O)N(R²²)—, —N(R²²)C(O)—, —S(O)₁₋₂N(R²²)—,—N(R²²)S(O)₁₋₂— or a bond;

L_((s)) and M_((t)) are independently selected from the group consistingof cycloalkylene, heterocycloalkylene, alkenylene, alkynylene, arylene,heteroarylene, or a bond; wherein the ring atoms of L and M areoptionally substituted with 1 to 5 R²⁴ groups independently selectedfrom the group consisting of H, alkyl, alkenyl, alkynyl, cycloalkyl,cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, aryl,arylalkyl, heteroaryl, heteroarylalkyl, arylcycloalkyl, halo, —CF₃, —SH,—OR¹⁹, —CN, —C(O)R²⁰, —C(O)OR¹⁹, —S(O)₀₋₂R²¹, —S(O)₁₋₂N(R²²)(R²³),—C(O)N(R²²)(R²³), —N(R²²)C(O)R²⁰, —N(R²²)C(O)N(R²²)(R²³),—N(R²²)C(O)OR¹⁹, —N(R²²)S(O)₁₋₂R²¹, —NO₂, —N═C(R²²)(R²³) and—N(R²²)(R²³); wherein s is 1 or 2 and t is 1 or 2;

R¹⁹ is H, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, cycloalkylalkyl,heteroaryl, arylalkyl, heteroarylalkyl, heterocycloalkyl orheterocycloalkylalkyl;

R²⁰ is H, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, cycloalkylalkyl,heteroaryl, arylalkyl, heteroarylalkyl, heterocycloalkyl,heterocycloalkylalkyl or —N(R²³)(R²⁴);

R²¹ is alkyl, alkenyl, alkynyl, aryl, cycloalkyl, cycloalkylalkyl,heteroaryl, arylalkyl, heteroarylalkyl, heterocycloalkyl orheterocycloalkylalkyl;

R²² and R²³ are H, alkyl, alkenyl, alkynyl, aryl, cycloalkyl,cycloalkylalkyl, heteroaryl, arylalkyl, heteroarylalkyl,heterocycloalkyl or heterocycloalkylalkyl;

provided that (i) when U is a bond, —O— or —N(R⁵)—, then R² is notselected from the group consisting of halo, —SH, —OR¹⁹, —S(O)₀₋₂R²¹,—S(O)₁₋₂N(R²²)(R²³), —N(R²²)C(O)R²⁰, —N(R²²)C(O)N(R²²)(R²³),—N(R²²)C(O)OR¹⁹, —N(R²²)S(O)₁₋₂R²¹, —NO₂, —N═C(R²²)(R²³) and—N(R²²)(R²³);

(ii) when W is —O(C(R³)(R⁴))_(a)— or —N(R⁵)(C(R³)(R⁴))_(a)— and a is 0,then R² is not selected from the group consisting of halo, —SH, —OR¹⁹,—S(O)₀₋₂R²¹, —S(O)₁₋₂N(R²²)(R²³), —N(R²²)C(O)R²⁰,—N(R²²)C(O)N(R²²)(R²³), —N(R²²)C(O)OR¹⁹, —N(R²²)S(O)₁₋₂R²¹, —NO₂,—N═C(R²²)(R²³) and —N(R²²)(R²³);

(iii) when W is —O(C(R³)(R⁴))_(a)— or —N(R⁵)(C(R³)(R⁴))_(a)— and a is 1or 2, then R³ and R⁴ on the carbon atom adjacent to the heteroatom of W,are not selected from the group consisting of halo, —SH, —OR¹⁹,—S(O)₀₋₂R²¹, —S(O)₁₋₂N(R²²)(R²³), —N(R²²)C(O)R²⁰,—N(R²²)C(O)N(R²²)(R²³), —N(R²²)C(O)OR¹⁹, —N(R²²)S(O)₁₋₂R²¹, —NO₂,—N═C(R²²)(R²³) and —N(R²²)(R²³);

(iv) when U is a bond, —O— or —N(R⁵)— and c is 0, then Z is not —O—,—N(R⁵)—, —S(O)₀₋₂—, —N(R²²)C(O)—, —S(O)₁₋₂N(R²²)— or —N(R²²)S(O)₁₋₂—;

(iv) when W is —O(C(R³)(R⁴))_(a)— or —N(R⁵)(C(R³)(R⁴))_(a)— and a and care 0, then Z is not —O—, —N(R⁵)—, —S(O)₀₋₂—, —N(R²²)C(O)—,—S(O)₁₋₂N(R²²)— or —N(R²²)S(O)₁₋₂—;

(v) when Z is —O— or —N(R⁵)—, then R⁷, R⁸, R⁹ and R¹⁰ on the carbon atomadjacent to Z are not selected from the group consisting of halo —SH,—OR¹⁹, —S(O)₀₋₂R²¹, —S(O)₁₋₂N(R²²)(R²³)—N(R²²)C(O)R²⁰,—N(R²²)C(O)N(R²²)(R²³), —N(R²²)C(O)OR¹⁹, —N(R²²)S(O)₁₋₂R²¹, —NO₂,—N═C(R²²)(R²³) and —N(R²²)(R²³);

(vi) when Y is —O— or —N(R⁵)—, then R¹¹, R¹², R¹³ and R¹⁴ on the carbonatom adjacent to Y are not selected from the group consisting of halo,—SH, —OR¹⁹, —S(O)₀₋₂R²¹, —S(O)₁₋₂N(R²²)(R²³), —N(R²²)C(O)R²⁰,—N(R²²)C(O)N(R²²)(R²³), —N(R²²)C(O)OR¹⁹, —N(R²²)S(O)₁₋₂R²¹, —NO₂,—N═C(R²²)(R²³) and —N(R²²)(R²³);

(vii) when X is —O— or —N(R⁵)—, then R¹⁵, R¹⁶, R¹⁷ and R¹⁸ on the carbonatom adjacent to X are not selected from the group consisting of halo,—SH, —OR¹⁹, —S(O)₀₋₂R²¹, —S(O)₁₋₂N(R²²)(R²³), —N(R²²)C(O)R²⁰,—N(R²²)C(O)N(R²²)(R²³), —N(R²²)C(O)OR¹⁹, —N(R²²)S(O)₁₋₂R²¹, —NO₂,—N═C(R²²)(R²³) and —N(R²²)(R²³);

(viii) when d and e are both zero and M is a bond, then Z or Y cannotboth be —O—;

(ix) when f and g are both zero and L is a bond, then Y or X cannot bothbe —O—;

(x) when h is 1, then X is not —O— or —N(R⁵)—;

(xi) X, L, M, Y, Z and the carbon atoms of —(C(R¹⁷)(R¹⁸))_(h)—,—(C(R¹⁵)(R¹⁶))_(g)—, —(C(R¹³)(R¹⁴))_(f)—, —(C(R¹¹)(R¹²))_(e)—,—(C(R⁹)(R¹⁰))_(d)— and —(C(R⁷)(R⁸))_(c)—, together with W, the carbon of—C(R²)— and the nitrogen atom to which W is attached form a ring of atleast 5 atoms;

(xii) when W is a bond, then the ring formed by X, L, M, Y, Z and thecarbon atoms of —(C(R¹⁷)(R¹⁸))_(h)—, —(C(R¹⁵)(R¹⁶))_(g)—,—(C(R¹³)(R¹⁴))_(f)—, —(C(R¹¹)(R¹²))_(e)—, —(C(R⁹)(R¹⁰))_(d)—,—(C(R⁷)(R⁸))_(c)—, W, the carbon of —C(R²)— and the nitrogen atomattached to W, has a ring size greater than 9 atoms;

and wherein each of the alkyl, alkenyl, alkynyl, cycloalkyl,cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, aryl,arylalkyl, heteroaryl, heteroarylalkyl, arylcycloalkyl groups in theabove definitions is independently unsubstituted or substituted by 1 to5 R²⁶ moieties independently selected from the group consisting ofalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl,heterocycloalkyl, heterocycloalkylalkyl, aryl, arylalkyl, heteroaryl,heteroarylalkyl, arylcycloalkyl, halo, haloalkyl, haloalkoxy, —CN, —CF₃,—SH, —OR¹⁹, —CN, —CH(R²²)R²³), —C(O)R²⁰, —C(O)OR¹⁹, —C(═NOR¹⁹)R²²,—P(O)(OR¹⁹)(OR¹⁹), —S(O)₀₋₂R²¹, —S(O)₁₋₂N(R²²)(R²³), —C(O)N(R²²)(R²³),—N(R²²)C(O)R²⁰, -alkyl-N(R²²)C(O)R²⁰, —N(R²²)C(O)N(R²²)(R²³),-alkyl-N(R²²)C(O)N(R²²)(R²³), —CH₂—R²², —N(R²²)C(O)OR¹⁹,—N(R²²)S(O)₁₋₂R²¹, —N(R²²)S(O)₁₋₂ N(R²²)(R²³), —N₃, —NO₂,—N═C(R²²)(R²³), ═NOR¹⁹—N(R²²)(R²³) and -alkyl-N(R²²)(R²³);

wherein each of the alkyl, alkenyl, alkynyl, cycloalkyl,cycloalkylalkyl, cycloalkenyl, heterocycloalkyl, heterocycloalkylalkyl,aryl, arylalkyl, heteroaryl, heteroarylalkyl, arylcycloalkyl, halo,haloalkyl and haloalkoxy in the above R²⁶ group is independentlyunsubstituted or substituted by 1 to 5 R²⁷ moieties independentlyselected from the group consisting of alkyl, alkenyl, alkynyl,cycloalkyl, cycloalkylalkyl, cycloalkenyl, heterocycloalkyl,heterocycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl,arylcycloalkyl, halo, haloalkyl, haloalkoxy, —CN, —CF₃, —SH, —OR¹⁹, —CN,—CH(R²²)R²³), —C(O)R²⁰, —C(O)OR¹⁹, —C(═NOR¹⁹)R²², —P(O)(OR¹⁹)(OR¹⁹),—S(O)₀₋₂R²¹, —S(O)₁₋₂N(R²²)(R²³), —C(O)N(R²²)(R²³), —N(R²²)C(O)R²⁰,-alkyl-N(R²²)C(O)R²⁰, —N(R²²)C(O)N(R²²)(R²³),-alkyl-N(R²²)C(O)N(R²²)(R²³), —CH₂—R²², —N(R²²)C(O)OR¹⁹,—N(R²²)S(O)₁₋₂R²¹, —N(R²²)S(O)₁₋₂ N(R²²)(R²³), —N₃, —NO₂,—N═C(R²²)(R²³), ═NOR¹⁹—N(R²²)(R²³) and -alkyl-N(R²²)(R²³).

In another aspect, the invention relates to a pharmaceutical compositioncomprising at least one compound of formula I and a pharmaceuticallyacceptable carrier.

In another aspect, the invention comprises the method of inhibitingaspartyl proteases comprising administering at least one compound offormula I to a patient in need of such treatment.

More specifically, the invention comprises: the method of treating acardiovascular disease such as hypertension, renal failure, congestiveheart failure or another disease modulated by renin inhibition; themethod of treating Human Immunodeficiency Virus; the method of treatinga cognitive or neurodegenerative disease such as Alzheimer's Disease;the method of inhibiting plasmepsins I and II for treatment of malaria;the method of inhibiting Cathepsin D for the treatment of Alzheimer'sDisease, breast cancer, and ovarian cancer; and the method of inhibitingprotozoal enzymes, for example inhibition of plasmodium falciparnum, forthe treatment of fungal infections. Said method of treatment compriseadministering at least one compound of formula I to a patient in need ofsuch treatment. In particular, the invention comprises the method oftreating Alzheimer's Disease comprising administering at least onecompound of formula I to a patient in need of such treatment.

In another aspect, the invention comprises the method of treatingAlzheimer's Disease comprising administering to a patient in need ofsuch treatment a combination of at least one compound of formula I and acholinesterase inhibitor or a muscarinic m₁ agonist or m₂ antagonist.

In a final aspect, the invention relates to a kit comprising in separatecontainers in a single package pharmaceutical compositions for use incombination, in which one-container comprises a compound of formula I ina pharmaceutically acceptable carrier and a second container comprises acholinesterase inhibitor or a muscarinic m₁ agonist or m₂ antagonist ina pharmaceutically acceptable carrier, the combined quantities being aneffective amount to treat a cognitive disease or neurodegenerativedisease such as Alzheimer's Disease.

DETAILED DESCRIPTION

In general, it is understood that divalent groups, for example, but notnecessarily limited to, —C(O)(C(R³)(R⁴))_(a)— are to be read left toright.

Preferred compounds of formula I are those compounds wherein W is—C(O)(C(R³)(R⁴))_(a)—.

Alternatively, another group of preferred compounds of formula I arethose compounds wherein a is 0.

Another group of preferred compounds of formula I are those compoundswherein a is 1.

Another group of preferred compounds of formula I are those compoundswherein c, d, f and h are each 0.

More preferred compounds of the invention are those compounds of formulaI, wherein e is 2-4.

More preferred compounds of the invention are those compounds of formulaI, wherein g is 1.

More preferred compounds of the invention are those compounds of formulaI, wherein X and Z are each a bond.

More preferred compounds of the invention are those compounds of formulaI, wherein Y is —C(O)N(R²²)— or —C(O)—.

Another group of preferred compounds of formula I are those compoundswherein Y is —C(O)— or —S(O)₁₋₂—.

Another group of preferred compounds of formula I are those compoundswherein L is a heterocycloalkylene group.

In yet another group of preferred compounds of formula I are thosecompounds wherein L and M are arylene or heteroarylene groups optionallysubstituted with 1 to 5 R²⁴ moieties.

Another group of preferred compounds of formula I are those compoundswherein M is an arylene or heteroarylene group optionally substitutedwith 1 to 5 R²⁴ moieties.

Another group of preferred compounds of formula I are those compoundswherein c is 1-2 or wherein d, f and h are 0.

In yet another group of preferred compounds of formula I are thosecompounds wherein L is an arylene or heteroarylene groups optionallysubstituted with 1 to 5 R²⁴ moieties.

In yet another group of preferred compounds of formula I are thosecompounds wherein L is a heterocycloalkylene group optionallysubstituted with 1 to 5 R²⁴ moieties.

In yet another group of preferred compounds of formula I are thosecompounds wherein M is an arylene or heteroarylene group optionallysubstituted with 1 to 3 R²⁴ moieties.

In yet another group of preferred compounds of formula I are thosecompounds wherein L is an arylene or heteroarylene groups optionallysubstituted with 1 to 5 R²⁴ moieties.

In yet another group of preferred compounds of formula I are thosecompounds wherein M is a heterocycloalkylene group optionallysubstituted with 1 to 5 R²⁴ moieties.

Compounds of formula I are those compounds wherein R² and R²⁴ are asdefined above and U is a bond; W is —C(O)(C(R³)(R⁴))_(a)—; a is 0; c, d,f and h are 0; e is 2-4; g is 1; X and Z are each a bond; Y is—C(O)N(R²²)— or —C(O)—; and L and M are arylene or heteroarylene groupsoptionally substituted with 1 to 5 R²⁴ moieties.

More preferred compounds of the invention are those compounds of formulaI, wherein R² and R²⁴ are as defined above and U is a bond; W is—C(═O)(C(R³)(R⁴))_(a)—; a is 0; c, d, f and h are 0; e is 2-4; g is 1; Xand Z are each a bond; Y is —C(O)— or —S(O)₁₋₂—; L is aheterocycloalkylene group, and M is an arylene or heteroarylene groupoptionally substituted with 1 to 5 R²⁴ moieties.

More preferred compounds of the invention are those compounds of formula1, wherein M, R² and R²⁴ are as defined above and U is a bond; W is—C(═O)(C(R³)(R⁴))_(a)—; a is 0; d, f and h are 0; c is 1-2; e is 2-4; gis 1; X and Z are each a bond; Y is —C(O)N(R²²)— or —C(O)—; and L is anarylene or heteroarylene groups optionally substituted with 1 to 5 R²⁴moieties.

Another group of preferred compounds of formula I are those compoundswherein M, R² and R²⁴ are as defined above and U is a bond; W is—C(═O)(C(R³)(R⁴))_(a)—; a is 0; d, f and h are 0; c is 1-2; e is 2-4; gis 1; X and Z are each a bond; Y is —C(O)— or —S(O)₁₋₂—; and L is aheterocycloalkylene group optionally substituted with 1 to 5 R²⁴moieties.

In yet another group of preferred compounds of formula I are thosecompounds wherein R² and R²⁴ are as defined above and U is a bond; W is—C(═O)(C(R³)(R⁴))_(a)—; a is 1; c, d, f and h are 0; e is 2-4; g is 1; Xand Z are each a bond, Y is —C(O)N(R²²)— or —C(O)—; and L and M arearylene or heteroarylene groups optionally substituted with 1 to 5 R²⁴moieties.

In yet another group of preferred compounds of formula I are thosecompounds wherein R² and R²⁴ are as defined above and U is a bond, W is—C(═O)(C(R³)(R⁴))_(a)—, a is 1; c, d, f and h are 0; e is 2-4, g is 1; Xand Z are each a bond, Y is —C(O)— or —S(O)₁₋₂—; and L is aheterocycloalkylene group, and M is an arylene or heteroarylene groupoptionally substituted with 1 to 3 R²⁴ moieties.

In another preferred embodiment are those compounds of formula I whereinM, R² and R²⁴ are as defined above, U is a bond; W is—C(═O)(C(R³)(R⁴))_(a)—; a is 1; d, f and h are 0; c is 1-2; e is 2-4; gis 1; X and Z are each a bond, Y is —C(O)N(R²²)— or —C(O)—; and L is anarylene or heteroarylene groups optionally substituted with 1 to 5 R²⁴moieties.

In yet another preferred embodiment are those compounds of formula Iwherein M, R² and R²⁴ are as defined above, U is a bond; W is—C(═O)(C(R³)(R⁴))_(a)—; a is 1; d, f and h are 0; c is 1-2; e is 2-4; gis 1; X and Z are each a bond, Y is —C(O)— or —S(O)₁₋₂—; and L is aheterocycloalkylene group optionally substituted with 1 to 5 R²⁴moieties.

It is noted that the carbons of formula I may be replaced with 1 to 3silicon atoms so long as all valency requirements are satisfied.

As used above, and throughout the specification, the following terms,unless otherwise indicated, shall be understood to have the followingmeanings:

“Patient” includes both human and animals.

“Mammal” means humans and other mammalian animals.

“Alkyl” means an aliphatic hydrocarbon group which may be straight orbranched and comprising about 1 to about 20 carbon atoms in the chain.Preferred alkyl groups contain about 1 to about 12 carbon atoms in thechain. More preferred alkyl groups contain about 1 to about 6 carbonatoms in the chain. Branched means that one or more lower alkyl groupssuch as methyl, ethyl or propyl, are attached to a linear alkyl chain.“Lower alkyl” means a group having about 1 to about 6 carbon atoms inthe chain which may be straight or branched. Non-limiting examples ofsuitable alkyl groups include methyl, ethyl, n-propyl, isopropyl,n-butyl, t-butyl, n-pentyl, heptyl, nonyl and decyl.

“Alkenyl” means an aliphatic hydrocarbon group containing at least onecarbon-carbon double bond and which may be straight or branched andcomprising about 2 to about 15 carbon atoms in the chain. Preferredalkenyl groups have about 2 to about 12 carbon atoms in the chain; andmore preferably about 2 to about 6 carbon atoms in the chain. Branchedmeans that one or more lower alkyl groups such as methyl, ethyl orpropyl, are attached to a linear alkenyl chain. “Lower alkenyl” meansabout 2 to about 6 carbon atoms in the chain which may be straight orbranched. Non-limiting examples of suitable alkenyl groups includeethenyl, propenyl, n-butenyl, 3-methylbut-2-enyl, n-pentenyl, octenyland decenyl.

“Alkynyl” means an aliphatic hydrocarbon group containing at least onecarbon-carbon triple bond and which may be straight or branched andcomprising about 2 to about 15 carbon atoms in the chain. Preferredalkynyl groups have about 2 to about 12 carbon atoms in the chain; andmore preferably about 2 to about 4 carbon atoms in the chain. Branchedmeans that one or more lower alkyl groups such as methyl, ethyl orpropyl, are attached to a linear alkynyl chain. “Lower alkynyl” meansabout 2 to about 6 carbon atoms in the chain which may be straight orbranched. Non-limiting examples of suitable alkynyl groups includeethynyl, propynyl, 2-butynyl, 3-methylbutynyl, n-pentynyl, and decynyl.

“Aryl” means an aromatic monocyclic or multicyclic ring systemcomprising about 6 to about 14 carbon atoms, preferably about 6 to about10 carbon atoms. The aryl group can be optionally substituted with oneor more substituents (e.g., R¹⁸, R²¹, R²², etc.) which may be the sameor different, and are as defined herein or two substituents on adjacentcarbons can be linked together to form

Non-limiting examples of suitable aryl groups include phenyl andnaphthyl.

“Heteroaryl” means an aromatic monocyclic or multicyclic ring systemcomprising about 5 to about 14 ring atoms, preferably about 5 to about10 ring atoms, in which one to eight of the ring atoms is an elementother than carbon, for example nitrogen, oxygen or sulfur, alone or incombination. Preferred heteroaryls contain about 5 to about 6 ringatoms. The “heteroaryl” can be optionally substituted by one or more R²¹substituents which may be the same or different, and are as definedherein. The prefix aza, oxa or thia before the heteroaryl root namemeans that at least a nitrogen, oxygen or sulfur atom respectively, ispresent as a ring atom. A nitrogen atom of a heteroaryl can beoptionally oxidized to the corresponding N-oxide. Non-limiting examplesof suitable heteroaryls include pyridyl, pyrazinyl, furanyl, thienyl,pyrimidinyl, isoxazolyl, isothiazolyl, oxazolyl, thiazolyl, pyrazolyl,furazanyl, pyrrolyl, pyrazolyl, triazolyl, 1,2,4-thiadiazolyl,pyrazinyl, pyridazinyl, quinoxalinyl, phthalazinyl,imidazo[1,2-a]pyridinyl, imidazo[2,1-b]thiazolyl, benzofurazanyl,indolyl, azaindolyl, benzimidazolyl, benzothienyl, quinolinyl,imidazolyl, thienopyridyl, quinazolinyl, thienopyrimidyl,pyrrolopyridyl, imidazopyridyl, isoquinolinyl, benzoazaindolyl,1,2,4-triazinyl, benzothiazolyl and the like.

“Cycloalkyl” means a non-aromatic mono- or multicyclic ring systemcomprising about 3 to about 10 carbon atoms, preferably about 5 to about10 carbon atoms. Preferred cycloalkyl rings contain about 5 to about 7ring atoms. The cycloalkyl can be optionally substituted with one ormore substituents which may be the same or different, and are as definedabove. Non-limiting examples of suitable monocyclic cycloalkyls includecyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl and the like.Non-limiting examples of suitable multicyclic cycloalkyls include1-decalin, norbornyl, adamantyl and the like. Further non-limitingexamples of cycloalkyl include the following

“Cycloalkylether” means a non-aromatic ring of 3 to 7 atoms comprisingan oxygen atom and 2 to 6 carbon atoms. Ring carbon atoms can besubstituted, provided that substituents adjacent to the ring oxygen donot include halo or substituents joined to the ring through an oxygen,nitrogen or sulfur atom.

“Cycloalkenyl” means a non-aromatic mono or multicyclic ring systemcomprising about 3 to about 10 carbon atoms, preferably about 5 to about10 carbon atoms which contains at least one carbon-carbon double bond.The cycloalkenyl ring can be optionally substituted with one or more R²¹substituents which may be the same or different, and are as definedabove. Preferred cycloalkenyl rings contain about 5 to about 7 ringatoms. Non-limiting examples of suitable monocyclic cycloalkenylsinclude cyclopentenyl, cyclohexenyl, cycloheptenyl, and the like.Non-limiting example of a suitable multicyclic cycloalkenyl isnorbornylenyl.

“Heterocyclenyl” means a non-aromatic monocyclic or multicyclic ringsystem comprising about 3 to about 14 ring atoms, preferably about 5 toabout 10 ring atoms, in which one or more of the atoms in the ringsystem is an element other than carbon, for example nitrogen, oxygen orsulfur atom, alone or in combination, and which contains at least onecarbon-carbon double bond or carbon-nitrogen double bond. There are noadjacent oxygen and/or sulfur atoms present in the ring system.Preferred heterocyclenyl rings contain about 5 to about 6 ring atoms.The prefix aza, oxa or thia before the heterocyclenyl root name meansthat at least a nitrogen, oxygen or sulfur atom respectively is presentas a ring atom. The heterocyclenyl can be optionally substituted by oneor more R²¹ substituents which may be the same or different. Thenitrogen or sulfur atom of the heterocyclenyl can be optionally oxidizedto the corresponding N-oxide, S-oxide or S,S-dioxide. Non-limitingexamples of suitable monocyclic azaheterocyclenyl groups include1,2,3,4-tetrahydropyridyl, 1,2-dihydropyridyl, 1,4-dihydropyridyl,1,2,3,6-tetrahydropyridyl, 1,4,5,6-tetrahydropyrimidyl, 2-pyrrolinyl,3-pyrrolinyl, 2-imidazolinyl, 2-pyrazolinyl, and the like. Non-limitingexamples of suitable oxaheterocyclenyl groups include3,4-dihydro-2H-pyran, dihydrofuranyl, fluorodihydrofuranyl, and thelike. Non-limiting example of a suitable multicyclic oxaheterocyclenylgroup is 7-oxabicyclo[2.2.1]heptenyl. Non-limiting examples of suitablemonocyclic thiaheterocyclenyl rings include dihydrothiophenyl,dihydrothiopyranyl, and the like.

“Halo” means fluoro, chloro, bromo, or iodo groups. Preferred arefluoro, chloro or bromo, and more preferred are fluoro and chloro.

“Haloalkyl” means an alkyl as defined above wherein one or more hydrogenatoms on the alkyl is replaced by a halo group defined above.

“Heterocyclyl” (or heterocycloalkyl) means a non-aromatic saturatedmonocyclic or multicyclic ring system comprising about 3 to about 10ring atoms, preferably about 5 to about 14 ring atoms, in which 1-3,preferably 1 or 2 of the atoms in the ring system is an element otherthan carbon, for example nitrogen, oxygen or sulfur, alone or incombination. There are no adjacent oxygen and/or sulfur atoms present inthe ring system. Preferred heterocyclyls contain about 5 to about 6 ringatoms. The prefix aza, oxa or thia before the heterocyclyl root namemeans that at least a nitrogen, oxygen or sulfur atom respectively ispresent as a ring atom. The heterocyclyl can be optionally substitutedby one or more R²¹ substituents which may be the same or different, andare as defined herein. The nitrogen or sulfur atom of the heterocyclylcan be optionally oxidized to the corresponding N-oxide, S-oxide orS,S-dioxide. Non-limiting examples of suitable monocyclic heterocyclylrings include piperidyl, pyrrolidinyl, piperazinyl, morpholinyl,thiomorpholinyl, thiazolidinyl, 1,3-dioxolanyl, 1,4-dioxanyl,tetrahydrofuranyl, tetrahydrothiophenyl, tetrahydrothiopyranyl, and thelike.

“Arylalkyl” means an aryl-alkyl-group in which the aryl and alkyl are aspreviously described. Preferred aralkyls comprise a lower alkyl group.Non-limiting examples of suitable aralkyl groups include benzyl,2-phenethyl and naphthamethyl. The bond to the parent moiety is throughthe alkyl.

“Arylcycloalkyl” means a group derived from a fused aryl and cycloalkylas defined herein. Preferred arylcycloalkyls are those wherein aryl isphenyl and cycloalkyl consists of about 5 to about 6 ring atoms. Thearylcycloalkyl can be optionally substituted by 1-5 R²¹ substituents.Non-limiting examples of suitable arylcycloalkyls include indanyl and1,2,3,4-tetrahydronaphthyl and the like. The bond to the parent moietyis through a non-aromatic carbon atom.

“Arylheterocycloalkyl” means a group derived from a fused aryl andheterocycloalkyl as defined herein. Preferred arylcycloalkyls are thosewherein aryl is phenyl and heterocycloalkyl consists of about 5 to about6 ring atoms. The arylheterocycloalkyl can be optionally substituted by1-5 R²¹ substituents. Non-limiting examples of suitablearylheterocycloalkyls include

The bond to the parent moiety is through a non-aromatic carbon atom.

Similarly, “heteroarylalkyl” “cycloalkylalkyl” and“heterocycloalkylalkyl” mean a heteroaryl-, cycloalkyl- orheterocycloalkyl-alkyl-group in which the heteroaryl, cycloalkyl,heterocycloalkyl and alkyl are as previously described. Preferred groupscontain a lower alkyl group. The bond to the parent moiety is throughthe alkyl.

“Acyl” means an H—C(O)—, alkyl-C(O)—, alkenyl-C(O)—, alkynyl-C(O)— orcycloalkyl-C(O)— group in which the various groups are as previouslydescribed. The bond to the parent moiety is through the carbonyl.Preferred acyls contain a lower alkyl. Non-limiting examples of suitableacyl groups include formyl, acetyl, propanoyl, 2-methylpropanoyl,butanoyl and cyclohexanoyl.

“Alkoxy” means an alkyl-O— group in which the alkyl group is aspreviously described. Non-limiting examples of suitable alkoxy groupsinclude methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy and heptoxy.The bond to the parent moiety is through the ether oxygen.

“Alkoxyalkyl” means a group derived from an alkoxy and alkyl as definedherein. The bond to the parent moiety is through the alkyl.

“Arylalkenyl” means a group derived from an aryl and alkenyl as definedherein. Preferred arylalkenyls are those wherein aryl is phenyl and thealkenyl consists of about 3 to about 6 atoms. The arylalkenyl can beoptionally substituted by one or more R²⁷ substituents. The bond to theparent moiety is through a non-aromatic carbon atom.

“Arylalkynyl” means a group derived from a aryl and alkynyl as definedherein. Preferred arylalkynyls are those wherein aryl is phenyl and thealkynyl consists of about 3 to about 6 atoms. The arylalkynyl can beoptionally substituted by one or more R²⁷ substituents. The bond to theparent moiety is through a non-aromatic carbon atom.

The suffix “ene” on alkyl, aryl, hetercycloalkyl, etc. indicates adivalent moiety, e.g., —CH₂CH₂— is ethylene, and

is para-phenylene.

It is understood that multicyclic divalent groups, for example,arylheterocycloalkylene, can be attached to other groups via bonds thatare formed on either ring of said group. For example,

The term “optionally substituted” means optional substitution with thespecified groups, radicals or moieties, in available position orpositions.

Substitution on a cycloalkylalkyl, heterocycloalkylalkyl, arylalkyl, orheteroarylalkyl moiety includes substitution on the ring portion and/oron the alkyl portion of the group.

When a variable appears more than once in a group, or a variable appearsmore than once in the structure of formula I, e.g., R⁵ may appear inboth U and W, the variables can be the same or different.

With reference to the number of moieties (e.g., substituents, groups orrings) in a compound, unless otherwise defined, the phrases “one ormore” and “at least one” mean that there can be as many moieties aschemically permitted, and the determination of the maximum number ofsuch moieties is well within the knowledge of those skilled in the art.With respect to the compositions and methods comprising the use of “atleast one compound of formula I,” one to three compounds of formula Ican be administered at the same time, preferably one.

As used herein, the term “composition” is intended to encompass aproduct comprising the specified ingredients in the specified amounts,as well as any product which results, directly or indirectly, fromcombination of the specified ingredients in the specified amounts.

The wavy line

as a bond generally indicates a mixture of, or either of, the possibleisomers, e.g., containing (R)- and (S)-stereochemistry. For example,

means containing both

Lines drawn into the ring systems, such as, for example:

indicate that the indicated line (bond) may be attached to any of thesubstitutable ring carbon atoms.

As well known in the art, a bond drawn from a particular atom wherein nomoiety is depicted at the terminal end of the bond indicates a methylgroup bound through that bond to the atom, unless stated otherwise. Forexample:

represents

It should also be noted that any heteroatom with unsatisfied valences inthe text, schemes, examples, structural formulae, and any Tables hereinis assumed to have the hydrogen atom or atoms to satisfy the valences.

Those skilled in the art will recognize that certain compounds offormula I are tautomeric, and all such tautomeric forms are contemplatedherein as part of the present invention.

Prodrugs and solvates of the compounds of the invention are alsocontemplated herein. A discussion of prodrugs is provided in T. Higuchiand V. Stella, Pro-drugs as Novel Delivery Systems (1987) 14 of theA.C.S. Symposium Series, and in Bioreversible Carriers in Drug Design,(1987) Edward B. Roche, ed., American Pharmaceutical Association andPergamon Press. The term “prodrug” means a compound (e.g, a drugprecursor) that is transformed in vivo to yield a compound of Formula(I) or a pharmaceutically acceptable salt, hydrate, ester or solvate ofthe compound. The transformation may occur by various mechanisms (e.g.,by metabolic or chemical processes), such as, for example, throughhydrolysis in blood. A discussion of the use of prodrugs is provided byT. Higuchi and W. Stella, “Pro-drugs as Novel Delivery Systems,” Vol. 14of the A.C.S. Symposium Series, and in Bioreversible Carriers in DrugDesign, ed. Edward B. Roche, American Pharmaceutical Association andPergamon Press, 1987.

For example, if a compound of Formula (I) or a pharmaceuticallyacceptable salt, hydrate, ester or solvate of the compound contains acarboxylic acid functional group, a prodrug can comprise an ester formedby the replacement of the hydrogen atom of the acid group with a groupsuch as, for example, (C₁-C₈)alkyl, (C₂-C₁₂)alkanoyloxymethyl,1-(alkanoyloxy)ethyl having from 4 to 9 carbon atoms,1-methyl-1-(alkanoyloxy)-ethyl having from 5 to 10 carbon atoms,alkoxycarbonyloxymethyl having from 3 to 6 carbon atoms,1-(alkoxycarbonyloxy)ethyl having from 4 to 7 carbon atoms,1-methyl-1-(alkoxycarbonyloxy)ethyl having from 5 to 8 carbon atoms,N-(alkoxycarbonyl)aminomethyl having from 3 to 9 carbon atoms,1-(N-(alkoxycarbonyl)amino)ethyl having from 4 to 10 carbon atoms,3-phthalidyl, 4-crotonolactonyl, gamma-butyrolacton-4-yl,di-N,N-(C₁-C₂)alkylamino(C₂-C₃)alkyl (such as β-dimethylaminoethyl),carbamoyl-(C₁-C₂)alkyl, N,N-di(C₁-C₂)alkylcarbamoyl-(C1-C2)alkyl andpiperidino-, pyrrolidino- or morpholino(C₂-C₃)alkyl, and the like.

Similarly, if a compound of Formula (I) contains an alcohol functionalgroup, a prodrug can be formed by the replacement of the hydrogen atomof the alcohol group with a group such as, for example,(C₁-C₆)alkanoyloxymethyl, 1-((C₁-C₆)alkanoyloxy)ethyl,1-methyl-1-((C₁-C₆)alkanoyloxy)ethyl, (C₁-C₆)alkoxycarbonyloxymethyl,N—(C₁-C₆)alkoxycarbonylaminomethyl, succinoyl, (C₁-C₆)alkanoyl,α-amino(C₁-C₄)alkanyl, arylacyl and α-aminoacyl, orα-aminoacyl-α-aminoacyl, where each α-aminoacyl group is independentlyselected from the naturally occurring L-amino acids, P(O)(OH)₂,—P(O)(O(C₁-C₆)alkyl)₂ or glycosyl (the radical resulting from theremoval of a hydroxyl group of the hemiacetal form of a carbohydrate),and the like.

If a compound of Formula (I) incorporates an amine functional group, aprodrug can be formed by the replacement of a hydrogen atom in the aminegroup with a group such as, for example, R-carbonyl, RO-carbonyl,NRR′-carbonyl where R and R′ are each independently (C₁-C₁₀)alkyl,(C₃-C₇)cycloalkyl, benzyl, or R-carbonyl is a natural α-aminoacyl ornatural α-aminoacyl, —C(OH)C(O)OY¹ wherein Y¹ is H, (C₁-C₆)alkyl orbenzyl, —C(OY²)Y³ wherein Y² is (C₁-C₄) alkyl and Y³ is (C₁-C₆)alkyl,carboxy(C₁-C₆)alkyl, amino(C₁-C₄)alkyl or mono-N- ordi-N,N-(C₁-C₆)alkylaminoalkyl, —C(Y⁴)Y⁵ wherein Y⁴ is H or methyl and Y⁵is mono-N— or di-N,N-(C₁-C₆)alkylamino morpholino, piperidin-1-yl orpyrrolidin-1-yl, and the like.

“Solvate” means a physical association of a compound of this inventionwith one or more solvent molecules. This physical association involvesvarying degrees of ionic and covalent bonding, including hydrogenbonding. In certain instances the solvate will be capable of isolation,for example when one or more solvent molecules are incorporated in thecrystal lattice of the crystalline solid. “Solvate” encompasses bothsolution-phase and isolatable solvates. Non-limiting examples ofsuitable solvates include ethanolates, methanolates, and the like.“Hydrate” is a solvate wherein the solvent molecule is H₂O.

“Effective amount” or “therapeutically effective amount” is meant todescribe an amount of compound or a composition of the present inventioneffective in inhibiting aspartyl protease and/or inhibiting BACE-1 andthus producing the desired therapeutic effect in a suitable patient.

The compounds of formula I form salts which are also within the scope ofthis invention. Reference to a compound of formula I herein isunderstood to include reference to salts thereof, unless otherwiseindicated. The term “salt(s)”, as employed herein, denotes acidic saltsformed with inorganic and/or organic acids, as well as basic saltsformed with inorganic and/or organic bases. In addition, when a compoundof formula I contains both a basic moiety, such as, but not limited to apyridine or imidazole, and an acidic moiety, such as, but not limited toa carboxylic acid, zwitterions (“inner salts”) may be formed and areincluded within the term “salt(s)” as used herein. Pharmaceuticallyacceptable (i.e., non-toxic, physiologically acceptable) salts arepreferred, although other salts are also useful. Salts of the compoundsof the formula I may be formed, for example, by reacting a compound offormula I with an amount of acid or base, such as an equivalent amount,in a medium such as one in which the salt precipitates or in an aqueousmedium followed by lyophilization. Acids (and bases) which are generallyconsidered suitable for the formation of pharmaceutically useful saltsfrom basic (or acidic) pharmaceutical compounds are discussed, forexample, by S. Berge et al, Journal of Pharmaceutical Sciences (1977)66(1) 1-19; P. Gould, International J. of Pharmaceutics (1986) 33201-217; Anderson et al, The Practice of Medicinal Chemistry (1996),Academic Press, New York; in The Orange Book (Food & DrugAdministration, Washington, D.C. on their website); and P. HeinrichStahl, Camille G. Wermuth (Eds.), Handbook of Pharmaceutical Salts:Properties, Selection, and Use, (2002) Int'l. Union of Pure and AppliedChemistry, pp. 330-331. These disclosures are incorporated herein byreference thereto.

Exemplary acid addition salts include acetates, adipates, alginates,ascorbates, aspartates, benzoates, benzenesulfonates, bisulfates,borates, butyrates, citrates, camphorates, camphorsulfonates,cyclopentanepropionates, digluconates, dodecylsulfates,ethanesulfonates, fumarates, glucoheptanoates, glycerophosphates,hemisulfates, heptanoates, hexanoates, hydrochlorides, hydrobromides,hydroiodides, 2-hydroxyethanesulfonates, lactates, maleates,methanesulfonates, methyl sulfates, 2-naphthalenesulfonates,nicotinates, nitrates, oxalates, pamoates, pectinates, persulfates,3-phenylpropionates, phosphates, picrates, pivalates, propionates,salicylates, succinates, bisulfates, sulfates, sulfonates (such as thosementioned herein), tartarates, thiocyanates, toluenesulfonates (alsoknown as tosylates,) undecanoates, and the like.

Exemplary basic salts include ammonium salts, alkali metal salts such assodium, lithium, and potassium salts, alkaline earth metal salts such ascalcium and magnesium salts, aluminum salts, zinc salts, salts withorganic bases (for example, organic amines) such as benzathines,diethylamine, dicyclohexylamines, hydrabamines (formed withN,N-bis(dehydroabietyl)ethylenediamine), N-methyl-D-glucamines,N-methyl-D-glucamides, t-butyl amines, piperazine,phenylcyclohexylamine, choline, tromethamine, and salts with amino acidssuch as arginine, lysine and the like. Basic nitrogen-containing groupsmay be quarternized with agents such as lower alkyl halides (e.g.methyl, ethyl, propyl, and butyl chlorides, bromides and iodides),dialkyl sulfates (e.g. dimethyl, diethyl, dibutyl, and diamyl sulfates),long chain halides (e.g. decyl, lauryl, myristyl and stearyl chlorides,bromides and iodides), aralkyl halides (e.g. benzyl and phenethylbromides), and others.

All such acid salts and base salts are intended to be pharmaceuticallyacceptable salts within the scope of the invention and all acid and basesalts are considered-equivalent to the free forms of the correspondingcompounds for purposes of the invention.

All stereoisomers (for example, geometric isomers, optical isomers andthe like) of the present compounds (including those of the salts,solvates and prodrugs of the compounds as well as the salts and solvatesof the prodrugs), such as those which may exist due to asymmetriccarbons on various substituents, including enantiomeric forms (which mayexist even in the absence of asymmetric carbons), rotameric forms,atropisomers, and diastereomeric forms, are contemplated within thescope of this invention. Individual stereoisomers of the compounds ofthe invention may, for example, be substantially free of other isomers,or may be admixed, for example, as racemates or with all other, or otherselected, stereoisomers. The chiral centers of the present invention canhave the S or R configuration as defined by the IUPAC 1974Recommendations. The use of the terms “salt”, “solvate”, “prodrug” andthe like, is intended to equally apply to the salt, solvate and prodrugof enantiomers, stereoisomers, rotamers, tautomers, racemates orprodrugs of the inventive compounds.

Polymorphic forms of the compounds of formula I, and of the salts,solvates and prodrugs of the compounds of formula I, are intended to beincluded in the present invention

Compounds of formula I can be made using procedures known in the art.The following reaction schemes show typical procedures, but thoseskilled in the art will recognize that other procedures can also besuitable.

In the Schemes and in the Example below, the following abbreviations areused:

high pressure liquid chromatography: HPLC

reverse-phase HPLC: RP-HPLC

liquid chromatography mass spectrometry: LCMS

mass spectrometry: MS

polytetrafluoroethylene: PTFE

hour: h

minute: min

retention time: t_(R)

ethyl: Et

methyl: Me

benzyl: Bn

lithium diisopropylamide: LDA

1-(3-dimethylaminopropyl)-3-ethyl carbodiimide hydrochloride: EDCl

DIEA means N,N-diisopropylethylamine

ethyl acetate: EtOAc

N,N-dimethylformamide: DMF

methanol: MeOH

Ethanol: EtOH

acetonitrile: CH₃CN

acetic acid: AcOH

magnesium sulfate: MgSO₄

copper iodide: CuI

diisopropylamine: ^(i)Pr₂NH

Dichlorobis(triphenylphosphine)palladium: PdCl₂(PPh₃)₂

ammonium hydroxide: NH₄OH

trifluoroacetic acid: TFA

benzyloxycarbonyl: Cbz

tert-butoxycarbonyl: Boc

In Schemes 1 to 3, the variable “R^(x)” is used in place of variablesR⁷-R¹⁸ in order to simplify the structures. “PG” refers to an amineprotecting group. Examples of suitable amine protecting groups are Bocand Cbz, as well as Bn for secondary amines.

In Schemes 2 to 5, the curved line,

represents a chain of substituted or unsubstituted carbons orheteroatoms numbering 4 to 8.

In Scheme 1, an appropriately substituted bromophenyl ketone II can beconverted into the corresponding hydantoin III under Bucherer-Bergsconditions. Base-mediated alkylation with suitable benzyl bromides orMitsunobu-coupling with appropriate benzyl alcohols can provide accessto derivative IV.

Coupling of aryl bromide IV with appropriately functionalized reagentsin palladium-mediated Heck-, Suzuki-, Stille or Sonogashira-typereactions can afford an intermediate that can be converted intocyclization precursor V via reduction with hydrogen over palladium. Vcan be subjected to a sequence of amine deprotection and cyclizationonto the ester or acid (examples of suitable R-groups in CO₂R are H, Me,Et) to afford macrocyclic hydantoin VI. Conversion of the imide carbonylgroup of VI with Lawesson's reagent can provide thiohydantoin VII, whichcan be subsequently subjected to oxidative amination conditions toafford desired iminohydantoin VIII.

In Scheme 2, hydantoin III can be hydrolyzed under basic conditions toamino acid IX, which can be subsequently converted into ester X underconditions such as MeOH/HCl or TMS-diazomethane/MeOH. Thioisocyanateformation with thiophosgene delivers isothiocyanate XI, which can bereacted with an appropriately functionalized amine XII to affordthiohydantoin XIII. Oxidative amination with an amine/tert-BuOOH canafford iminohydantoin XIV.

In Scheme 3, coupling of aryl bromide XIV with appropriatelyfunctionalized reagents in palladium-mediated Heck-, Suzuki-, Stille orSonogashira-type reactions can afford an intermediate that can beconverted into cyclization precursor XV via reduction with hydrogen overpalladium. XV can be subjected to a sequence of amine deprotection andcyclization onto the ester or acid (examples of suitable R-groups inCO₂R are H, Me, Et) to afford macrocyclic hydantoin XVI.

In Scheme 4, an appropriately substituted bromophenyl ketone II can becondensed with tert-butylsulfinamide, promoted by Lewis-acids such asTi(OEt)₄. The resulting imine XVII can be treated with an ester enolate,and the adduct can be hydrolyzed under acidic conditions to give aminomethylester XVIII. Coupling with thiourea XIX can afford iminopyrimidoneXX, which can be alkylated with suitable electrophiles such as R³X andR⁴X to give intermediate XXI.

In Scheme 5, coupling of aryl bromide XXI with appropriatelyfunctionalized reagents in palladium-mediated Heck-, Suzuki-, Stille orSonogashira-type reactions can afford an intermediate that can beconverted into a cyclization precursor XXII via reduction with hydrogenover palladium. XXII can be subjected to a sequence of aminedeprotection and cyclization onto the ester or acid (examples ofsuitable R-groups in CO₂R are H, Me, Et) to eventually affordmacrocyclic iminopyrimidinone XXIII after removal of theimino-protecting group.

The conditions for the RP-HPLC and LCMS analysis in the preparation andexample below can be as follows:Conditions A: 5 minute gradient from 10%→95% CH₃CN/H₂O with 0.1% TFA,then 2 min isocratic at 95% CH₃CN/H₂O with 0.1% TFA, 1.0 mL/min flowrate on an analytical C18 reverse-phase column.Conditions B: gradient from 10%→95% CH₃CN/H₂O with 0.1% HCO₂H, 30 mL/minflow rate on a preparative C18 reverse-phase column.

EXAMPLE 1 Synthesis of Macrocycle 7

5-(3-Bromo-phenyl)-5-methyl-imidazolidine-2,4-dione (1): To a suspensionof ammonium carbonate (20.5 g, 225 mmol) and potassium cyanide (8.6 g,125 mmol) in EtOH/water (160 mL, 1/1) at 23° C. was added3-bromoacetophenone (6.61 mL, 50 mmol). The pressure-tube was sealed andheated for 24 h at 95° C., then cooled to 23° C. The solution wasdiluted with water (300 mL), the solid removed by filtration and driedunder vacuum to give the desired material (11.3 g, 84%). MS (ES+):269/271 (M+H), 310/312 (M+H+CH₃CN).

3-[4-(3-Bromo-phenyl)-4-methyl-2,5-dioxo-imidazolidin-1-ylmethyl]-benzoicacid methyl ester (2): In analogy to the literature (Moloney et al., J.Med. Chem. 1997, 40, 2347-2362), methyl 3-bromomethylbenzoate (4.75 g,20.7 mmol) was added to a suspension of hydantoin 1 (5.0 g, 18.6 mmol)and potassium carbonate (3.1 g, 22.5 mmol) in DMF (75 mL) at 23° C.After 18 h, the reaction mixture was partitioned between water andEtOAc, and the aqueous layer extracted with EtOAc. The combined organiclayers were washed with water (1×), NaHCO₃ (1×), water (1×), brine (1×),then dried over MgSO₄. After filtration, concentration in vacuo gave anoil, which was subjected to silica gel chromatography (20→50%EtOAc/hexanes) to yield the desired material as a white sticky foam(8.32 g, 100%). ¹H NMR (400 MHz, CDCl₃) δ 7.92 (m, 2H), 7.58 (m, 1H),7.34-7.46 (m, 4H), 7.20 (m, 2H), 4.66 (s, 2H), 3.84 (s, 3H), 1.76 (s,3H).

3-(4-[3-(3-Benzyloxycarbonylamino-prop-1-ynyl)-phenyl]-4-methyl-2,5-dioxo-imidazolidin-1-ylmethyl)-benzoicacid methyl ester (3): A mixture of hydantoin 2 (830 mg, 2 mmol),N-Cbz-propargylamine (460 mg, 2.43 mmol; prepared according to theliterature by Yasuda et al., patent application 2003, US 2003/0004353),CuI (20 mg, 0.1 mol), PdCl₂(PPh₃)₂ (70 mg, 0.1 mmol) and iPr₂NH (850 μL,6 mmol) in DMF (5 mL) was heated for 15 min at 100° C. (Smith MicrowaveSynthesizer). The reaction mixture was diluted with EtOAc, washed with 1M HCl (2×), NaHCO₃ (1×), water (3×) and brine (1×), then dried overMgSO₄, filtered and concentrated under vacuum. The crude material wassubjected to silica gel chromatography (30→50% EtOAc/hexanes) to yieldthe desired material as a colorless film (598 mg, 57%). ¹H NMR (400 MHz,CDCl₃) δ 7.89 (m, 2H), 7.21-7.46 (m, 12H), 6.71 (bs, 1H), 4.62 (s, 2H),4.12 (m, 2H), 3.81 (s, 3H), 1.72 (s, 3H). MS (ES+): 526 (M+H).

3-{4-[3-(3-Amino-propyl)-phenyl]-4-methyl-2,5-dioxo-imidazolidin-1-ylmethyl}-benzoic acid methyl ester (4): A solution of theCbz-protected propargylamine 3 (580 mg, 1.1 mmol) and acetic acid (50μL) in MeOH (10 mL) was stirred over 10% Pd/C (284 mg) under anatmosphere of hydrogen (50 psi) for 18 h. The suspension was passedthrough a PTFE-filter and the resulting filtrate concentrated undervacuum to give the desired material as a yellow solid (440 mg, 100%). ¹HNMR (400 MHz, CDCl₃) δ 8.32 (bs, 1H), 8.05 (bs, 2H), 7.83-7.88 (m, 2H),7.34-7.41 (m, 3H), 7.27 (m, 1H), 7.14 (m, 1H), 6.95 (m, 1H), 4.57 (s,2H), 3.79 (s, 3H), 3.39 (m, 2H), 2.86 (m, 2H), 2.60 (m, 2H), 2.00 (m,2H), 1.65 (s, 3H). MS (ES+): 396 (M+H), 418 (M+Na).

2-Methyl-3,5,13-triazatetracyclo[15.3.1.1(2,5).1(7,11)]tricosa-1(21),7,9,11(22),17,19-hexaene-4,12,23-trione(5): A solution of amino methylester 4 (120 mg, 300 μmol) in MeOH (40mL) was heated in the presence of sodium methoxide (30 wt % solution inMeOH, 300 μL, 900 μmol) for 4 days at 85° C. The reaction mixture wascooled to 23° C., acidified with AcOH (50 μL) and concentrated in vacuoto give a solid that was subjected to RP-HPLC (conditions B) to give thedesired macrocycle as a white solid (52 mg, 48%). ¹H NMR (400 MHz,CD₃OD) δ 7.56 (m, 1H), 7.47-7.52 (m, 2H), 7.28-7.41 (m, 4H), 7.20 (m,1H), 6.79 (bs, 1H), 4.71 (s, 2H), 3.25-3.44 (m, 2H), 2.90-2.97 (m, 1H),2.60-2.67 (m, 1H), 2.12-2.17 (m, 1H), 1.96-2.03 (m, 1H), 1.80 (s, 3H).LCMS (Conditions A): t_(R)=2;78 min: 364.1 (M+H).

Thiohydantoin (6): A suspension of macrocyclic hydantoin 5 (50 mg, 137μmol) and Lawesson's reagent (66 mg, 165 μmol) in toluene (2 mL) washeated for 18 h at 95° C. in a sealed vial. After cooling the reactionto 23° C., the suspension was partitioned between EtOAc and NaHCO₃. Theaqueous phase was extracted with EtOAc (1×), and the combined organiclayers washed with NaHCO₃ (2×), water (1×) and brine (1×), then driedover MgSO₄, filtered and concentrated under vacuum. The crude materialwas subjected to RP-HPLC (conditions B) to give the desired macrocyclicthiohydantoin 6 (36 mg, 70%) along with dithiohydantoin (7 mg, 13%). ¹HNMR (400 MHz, CD₃OD) δ 7.65-7.78 (m, 3H, 7.44 (m, 1H), 7.22-7.40 (m,2H), 6.81-6.95 (m, 3H), 6.57 (m, 1H), 4.71 (m, 2H), 3.80 (m, 2H), 2.91(m, 1H), 2.69 (m, 1H), 2.34 (m, 1H), 2.19 (m, 1H), 1.81 (m, 3H). MS(ES+): 380 (M+H).

4-Imino-2-methyl-3,5,13-triazatetracyclo[15.3.1.1(2,5).1(7,11)]tricosa-1(21),7,9,11(22),17,19-hexaene-12,23-dione(7): To a suspension of macrocyclic thiohydantoin 6 (36 mg, 95 μmol) inMeOH (4 mL) at 23° C. was added concentrated NH₄OH solution (28% inwater, 1 mL) and tert-butylhydrogenperoxide (70% in water, 1 mL). Thereaction was stirred for 2 days at 23° C., then concentrated undervacuum. The residue was suspended in MeOH (2 mL), passed through aPTFE-filter and the filtrate subjected to RP-HPLC (conditions B) to givethe desired material. The formate salt resulting from the reverse-phaseHPLC was treated with 1 M HCl/MeOH for 15 min at 23° C., thenconcentrated to give the HCl-salt of macrocyclic iminohydantoin 7 as acolorless film (15.9 mg, 42%). ¹H NMR (400 MHz, CD₃OD) revealed thepresence of rotamers. LCMS (Conditions A): t_(R)=2.20 min: 363(M+H—HCl).

Human Cathepsin D FRET Assay

The substrate used below has been described (Y. Yasuda et al., J.Biochem., 125, 1137 (1999)). Substrate and enzyme are commerciallyavailable.

The assay can be run in a 30 μl final volume using a 384 well Nunc blackplate. 8 concentrations of compound can be pre-incubated with enzyme for30 mins at 37° C. followed by addition of substrate with continuedincubation at 37° C. for 45 mins. The rate of increase in fluorescenceis linear for over 1 h and is measured at the end of the incubationperiod using a Molecular Devices FLEX station plate reader. Kis areinterpolated from the IC50s using a Km value of 4 μM and the substrateconcentration of 2.5 μM.

Reagents

-   Na-Acetate pH 5-   1% Brij-35 from 10% stock (Calbiochem)-   DMSO-   Purified (>95%) human liver Cathepsin D (Athens Research &    Technology Cat# 16-12-030104)-   Peptide substrate (Km=4 uM)    Mca-Gly-Lys-Pro-lle-Leu-Phe-Phe-Arg-Leu-Lys(Dnp)-D-Arg-NH₂ Bachem    Cat # M-2455-   Pepstatin is used as a control inhibitor (Ki˜0.5 nM) and is    available from Sigma.-   Nunc 384 well black plates    Final Assay Buffer Conditions-   100 mM Na Acetate pH 5.0-   0.02% Brij-35-   1% DMSO    Compound can be diluted to 3× final concentration in assay buffer    containing 3% DMSO. 10 μl of compound will be added to 10 μl of 2.25    nM enzyme (3×) diluted in assay buffer without DMSO, mixed briefly,    spun, and can be incubated at 37° C. for 30 mins. 3× substrate (7.5    μM) is prepared in 1× assay buffer without DMSO. 10 μl of substrate    will be added to each well mixed and spun briefly to initiate the    reaction. Assay plates can be incubated at 37 C for 45 mins and read    on 384 compatible fluorescence plate reader using a 328 nm Ex and    393 nm Em.

BACE-1 Cloning, Protein Expression and Purification

A predicted soluble form of human BACE1 (sBACE1, corresponding to aminoacids 1-454) can be generated from the full length BACE1 cDNA (fulllength human BACE1 cDNA in pcDNA4/mycHisA construct; University ofToronto) by PCR using the advantage-GC cDNA PCR kit (Clontech, PaloAlto, Calif.). A HindIII/Pmel fragment from pcDNA4-sBACE1myc/His can beblunt ended using Klenow and subcloned into the Stu I site ofpFASTBACI(A) (Invitrogen). A sBACE1mycHis recombinant bacmid can begenerated by transposition in DH10Bac cells (GIBCO/BRL). Subsequently,the sBACE1 mycHis bacmid construct can be transfected into sf9 cellsusing CellFectin (Invitrogen, San Diego, Calif.) in order to generaterecombinant baculovirus. Sf9 cells are grown in SF 900-II medium(Invitrogen) supplemented with 3% heat inactivated FBS and 0.5×penicillin/streptomycin solution (Invitrogen). Five milliliters of hightiter plaque purified sBACEmyc/His virus is used to infect 1 L oflogarithmically growing sf9 cells for 72 hours. Intact cells arepelleted by centrifugation at 3000×g for 15 minutes. The supernatant,containing secreted sBACE1, is collected and diluted 50% v/v with 100 mMHEPES, pH 8.0. The diluted medium is loaded onto a Q-sepharose column.The Q-sepharose column is washed with Buffer A (20 mM HEPES, pH 8.0, 50mM NaCl).

Proteins, can be eluted from the Q-sepharose column with Buffer B (20 mMHEPES, pH 8.0, 500 mM NaCl). The protein peaks from the Q-sepharosecolumn are pooled and loaded onto a Ni-NTA agarose column. The Ni-NTAcolumn can be then washed with Buffer C (20 mM HEPES, pH 8.0, 500 mMNaCl). Bound proteins are then eluted with Buffer D (Buffer C+250 mMimidazole). Peak protein fractions as determined by the Bradford Assay(Biorad, CA) are concentrated using a Centricon 30 concentrator(Millipore). sBACE1 purity is estimated to be ˜90% as assessed bySDS-PAGE and Commassie Blue staining. N-terminal sequencing indicatesthat greater than 90% of the purified sBACE1 contained the prodomain;hence this protein is referred to as sproBACE1.

Peptide Hydrolysis Assay

The inhibitor, 25 nM EuK-biotin labeled APPsw substrate(EuK-KTEEISEVNLDAEFRHDKC-biotin; CIS-Bio International, France), 5 μMunlabeled APPsw peptide (KTEEISEVNLDAEFRHDK; American Peptide Company,Sunnyvale, Calif.), 7 nM sproBACE1, 20 mM PIPES pH 5.0, 0.1% Brij-35(protein grade, Calbiochem, San Diego, Calif.), and 10% glycerol arepreincubated for 30 min at 30° C. Reactions are initiated by addition ofsubstrate in a 5 μl aliquot resulting in a total volume of 25 μl. After3 hr at 30° C. reactions are terminated by addition of an equal volumeof 2× stop buffer containing 50 mM Tris-HCl pH 8.0, 0.5 M KF, 0.001%Brij-35, 20 μg/ml SA-XL665 (cross-linked allophycocyanin protein coupledto streptavidin; CIS-Bio International, France) (0.5 μg/well). Platesare shaken briefly and spun at 1200×g for 10 seconds to pellet allliquid to the bottom of the plate before the incubation. HTRFmeasurements are made on a Packard Discovery® HTRF plate reader using337 nm laser light to excite the sample followed by a 50 μs delay andsimultaneous measurements of both 620 nm and 665 nm emissions for 400μs.

IC₅₀ determinations for inhibitors, (I), are determined by measuring thepercent change of the relative fluorescence at 665 nm divided by therelative fluorescence at 620 nm, (665/620 ratio), in the presence ofvarying concentrations of I and a fixed concentration of enzyme andsubstrate. Nonlinear regression analysis of this data can be performedusing GraphPad Prism 3.0 software selecting four parameter logisticequation, that allows for a variable slope.Y=Bottom+(Top−Bottom)/(1+10^((LogEC50−X)*Hill Slope)); X is thelogarithm of concentration of 1, Y is the percent change in ratio and Ystarts at bottom and goes to top with a sigmoid shape.

Human Mature Renin Enzyme Assay

Human Renin can be cloned from a human kidney cDNA library andC-terminally epitope-tagged with the V5-6His sequence into pcDNA3.1.pCNDA3.1-Renin-V5-6His is stably expressed in HEK293 cells and purifiedto >80% using standard Ni-Affinity chromatography. The prodomain of therecombinant human renin-V5-6His can be removed by limited proteolysisusing immobilized TPCK-trypsin to give mature-human renin. Reninenzymatic activity can be monitored using a commercially availablefluorescence resonance energy transfer (FRET) peptide substrate, RS-1(Molecular Probes, Eugene, Oreg.) in 50 mM Tris-HCl pH 8.0, 100 mM NaCl,0.1% Brij-35 and 5% DMSO buffer for 40 mins at 30° celsius in thepresence or absence of different concentrations of test compounds.Mature human Renin is present at approximately 200 nM. Inhibitoryactivity is defined as the percent decrease in renin inducedfluorescence at the end of the 40 min incubation compared to vehiclecontrols and samples lacking enzyme.

In the aspect of the invention relating to a combination of at least onecompound of formula I with at least one cholinesterase inhibitor,acetyl- and/or butyrylcholinesterase inhibitors can be used. Examples ofcholinesterase inhibitors are tacrine, donepezil, rivastigmine,galantamine, pyridostigmine and neostigmine, with tacrine, donepezil,rivastigmine and galantamine being preferred. Preferably, thesecombinations are directed to the treatment of Alzheimer's Disease.

In one aspect of the invention, a combination of at least one compoundof formula I with at least one muscarinic m₁ agonist or m₂ antagonistcan be used. Examples of m₁ agonists are known in the art. Examples ofm₂ antagonists are also known in the art; in particular, m₂ antagonistsare disclosed in U.S. Pat. Nos. 5,883,096; 6,037,352; 5,889,006;6,043,255; 5,952,349; 5,935,958; 6,066,636; 5,977,138; 6,294,554;6,043,255; and 6,458,812; and in WO 03/031412, all of which areincorporated herein by reference.

In other aspects of the invention relating to a combination of at leastone compound of formula I and at least one other agent, for example abeta secretase inhibitor; a gamma secretase inhibitor; an HMG-CoAreductase inhibitor such as atorvastatin, lovastatin, simvastatin,pravastatin, fluvastatin and rosuvastatin; non-steroidalanti-inflammatory agents such as, but not necessarily limited toibuprofen, relafen or naproxen; N-methyl-D-aspartate receptorantagonists such as memantine; anti-amyloid antibodies includinghumanized monoclonal antibodies; vitamin E; nicotinic acetylcholinereceptor agonists; CB1 receptor inverse agonists or CB1 receptorantagonists; antibiotics such as doxycycline; growth hormonesecretagogues; histamine H3 antagonists; AMPA agonists; PDE4 inhibitors;GABA_(A) inverse agonists; inhibitors of amyloid aggregation; glycogensynthase kinase beta inhibitors; promoters of alpha secretase activity.Preferably, these combinations are directed to the treatment ofAlzheimer's Disease.

For preparing pharmaceutical compositions from the compounds describedby this invention, inert, pharmaceutically acceptable carriers can beeither solid or liquid. Solid form preparations include powders,tablets, dispersible granules, capsules, cachets and suppositories. Thepowders and tablets may be comprised of from about 5 to about 95 percentactive ingredient. Suitable solid carriers are known in the art, e.g.magnesium carbonate, magnesium stearate, talc, sugar or lactose.Tablets, powders, cachets and capsules can be used as solid dosage formssuitable for oral administration. Examples of pharmaceuticallyacceptable carriers and methods of manufacture for various compositionsmay be found in A. Gennaro (ed.), Remington's Pharmaceutical Sciences,18th Edition, (1990), Mack Publishing Co., Easton, Pa.

Liquid form preparations include solutions, suspensions and emulsions.As an example may be mentioned water or water-propylene glycol solutionsfor parenteral injection or addition of sweeteners and opacifiers fororal solutions, suspensions and emulsions. Liquid form preparations mayalso include solutions for intranasal administration.

Aerosol preparations suitable for inhalation may include solutions andsolids in powder form, which may be in combination with apharmaceutically acceptable carrier, such as an inert compressed gas,e.g. nitrogen.

Also included are solid form preparations which are intended to beconverted, shortly before use, to liquid form preparations for eitheroral or parenteral administration. Such liquid forms include solutions,suspensions and emulsions.

The compounds of the invention may also be deliverable transdermally.The transdermal compositions can take the form of creams, lotions,aerosols and/or emulsions and can be included in a transdermal patch ofthe matrix or reservoir type as are conventional in the art for thispurpose.

Preferably the compound is administered orally.

Preferably, the pharmaceutical preparation is in a unit dosage form. Insuch form, the preparation is subdivided into suitably sized unit dosescontaining appropriate quantities of the active component, e.g., aneffective amount to achieve the desired purpose.

The quantity of active compound in a unit dose of preparation may bevaried or adjusted from about 1 mg to about 100 mg, preferably fromabout 1 mg to about 50 mg, more preferably from about 1 mg to about 25mg, according to the particular application.

The actual dosage employed may be varied depending upon the requirementsof the patient and the severity of the condition being treated.Determination of the proper dosage regimen for a particular situation iswithin the skill of the art. For convenience, the total daily dosage maybe divided and administered in portions during the day as required.

The amount and frequency of administration of the compounds of theinvention and/or the pharmaceutically acceptable salts thereof will beregulated according to the judgment of the attending clinicianconsidering such factors as age, condition and size of the patient aswell as severity of the symptoms being treated. A typical recommendeddaily dosage regimen for oral administration can range from about 1mg/day to about 300 mg/day, preferably 1 mg/day to 50 mg/day, in two tofour divided doses.

When a compound of formula I is used in combination with acholinesterase inhibitor to treat cognitive disorders, these two activecomponents may be co-administered simultaneously or sequentially, or asingle pharmaceutical composition comprising a compound of formula I anda cholinesterase inhibitor in a pharmaceutically acceptable carrier canbe administered. The components of the combination can be administeredindividually or together in any conventional oral or parenteral dosageform such as capsule, tablet, powder, cachet, suspension, solution,suppository, nasal spray, etc. The dosage of the cholinesteraseinhibitor can be determined from published material, and may range from0.001 to 100 mg/kg body weight.

When separate pharmaceutical compositions of a compound of formula I anda cholinesterase inhibitor are to be administered, they can be providedin a kit comprising in a single package, one container comprising acompound of formula I in a pharmaceutically acceptable carrier, and aseparate container comprising a cholinesterase inhibitor in apharmaceutically acceptable carrier, with the compound of formula I andthe cholinesterase inhibitor being present in amounts such that thecombination is therapeutically effective. A kit is advantageous foradministering a combination when, for example, the components must beadministered at different time intervals or when they are in differentdosage forms.

While the present invention has been described in conjunction with thespecific embodiments set forth above, many alternatives, modificationsand variations thereof will be apparent to those of ordinary skill inthe art. All such alternatives, modifications and variations areintended to fall within the spirit and scope of the present invention.

1. A compound having the structural formula

or a pharmaceutically acceptable salt or ester thereof, wherein R¹ isselected from the group consisting of H, alkyl, alkenyl, alkynyl,cycloalkyl, cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl,aryl, arylalkyl, heteroaryl, heteroarylalkyl, arylcycloalkyl, —OR¹⁹,—CN, —C(O)R²⁰, —C(O)OR¹⁹, —S(O)₁₋₂R²¹, —C(O)N(R²²)(R²³),—S(O)₁₋₂N(R²²)(R²³), —NO₂, —N═C(R²²)(R²³) and —N(R²²)(R²³); R² isselected from the group consisting of H, alkyl, alkenyl, alkynyl,cycloalkyl, cycloalkylal kyl, heterocycloalkyl, heterocycloalkylalkyl,aryl, arylalkyl, heteroaryl, heteroarylalkyl, arylcycloalkyl, —CF₃, —CN,—C(O)R²⁰, —C(O)OR¹⁹, and —C(O)N(R²²)(R²³); e is 3; R¹¹ and R¹² are eachindependently selected from the group consisting of H, alkyl, alkenyl,alkynyl, cycloalkyl, cycloalkylalkyl, heterocycloalkyl,heterocycloalkylalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl,arylcycloalkyl, halo, —CF₃ —SH, —OR¹⁹, —CN, —C(O)R²⁰, —C(O)OR¹⁹,—S(O)₀₋₂R²¹, —S(O)₁₋₂N(R²²)(R²³), —C(O)N(R²²)(R²³), —N(R²²)C(O)R²⁰,—N(R²²)C(O)N(R²²)(R²³), —N(R²²)C(O)OR¹⁹, —N(R²²)S(O)₁₋₂R²¹, —NO₂,—N═C(R²²)(R²³) and —N(R²²)(R²³), Y is selected from the group consistingof —O—, —N(R⁵)—. —C(O)—. —S(O)₀₋₂—, —C(O)N(R²²)—. —N(R²²)C(O)—.—S(O)₁₋₂N(R²²)—, —N(R²²)S(O)₁₋₂— or a bond; R¹⁹ is H, alkyl, alkenyl,alkynyl, aryl, cycloalkyl, cycloalkylalkyl, heteroaryl, arylalkyl,heteroarylalkyl, heterocycloalkyl or heterocycloalkylalkyl; R²⁰ is H,alkyl, alkenyl, alkynyl, aryl, cycloalkyl, cycloalkylalkyl, heteroaryl,arylalkyl, heteroarylalkyl, heterocycloalkyl, heterocycloalkylalkyl,—NH₂, —NH(alkyl), or —N(alkyl)_(2;) R²¹ is alkyl, alkenyl, alkynyl,aryl, cycloalkyl, cycloalkylalkyl, heteroaryl, arylalkyl,heteroarylalkyl, heterocycloalkyl or heterocycloalkylalkyl; R²² and R²³are H, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, cycloalkylalkyl,heteroaryl, arylalkyl, heteroarylalkyl, heterocycloalkyl orheterocycloalkylalkyl; and each R²⁴ is independently selected from thegroup consisting of H, alkyl, alkenyl, alkynyl, cycloalkyl,cycloalkylalkyl, heterocycloalkyl, heterocycloalkylalkyl, aryl,arylalkyl, heteroaryl, heteroarylalkyl, arylcycloalkyl, halo, —CF₃, —SH,—OR¹⁹, —CN, —C(O)R²⁰, —C(O)OR¹⁹, —S(O)₀₋₂R²¹, —S(O)₁₋₂N(R²²)(R²³),—C(O)N(R²²)(R²³), —N(R²²)C(O)R²⁰, —N(R²²)C(O)N(R²²)(R²³),—N(R²²)C(O)OR¹⁹, —N(R²²)S(O)₁₋₂R²¹, —NO₂, —N═C(R²²)(R²³) and—N(R²²)(R²³); wherein s is 1 or 2 and t is 1 or
 2. 2. A compound ofclaim 1, or a pharmaceutically acceptable salt or ester thereof, whereinY is —C(O)N(R²²)— or —N(R²²)C(O)—.
 3. A compound of claim 1 wherein Y is—C(O)N(R²²)—.
 4. A compound according to claim 1, or a pharmaceuticallyacceptable salt or ester thereof, with the following structure


5. A pharmaceutical composition comprising an effective amount of acompound of claim 1, or a pharmaceutically acceptable salt or esterthereof, and a pharmaceutically effective carrier.
 6. A pharmaceuticalcomposition comprising an effective amount of a compound of claim 1, andan effective amount of a cholinesterase inhibitor or a muscarinic m₁agonist or m₂ antagonist, in a pharmaceutically effective carrier.
 7. Apharmaceutical composition comprising an effective amount of a compoundof claim 1, and an effective amount of a gamma secretase inhibitor; anHMG-CoA red uctase inhibitor or a non-steroidal anti-inflammatory agent.8. A pharmaceutical composition comprising an effective amount of acompound of claim 4, or a pharmaceutically acceptable salt or esterthereof, and a pharmaceutically effective carrier.
 9. A compound ofclaim 1, wherein R¹ is selected from the group consisting of H andalkyl.
 10. A compound of claim 1, wherein R¹ is H.
 11. A compound ofclaim 1, wherein R² is selected from the group consisting of H, alkyl,cycloalkyl, cycloalkylalkyl, aryl, arylalkyl, heteroaryl,heteroarylalkyl, —CF_(3,) —CN, —C(O)R²⁰, —C(O)OR¹⁹, and—C(O)N(R²²)(R²³).
 12. A compound of claim 1, wherein R² is selected fromthe group consisting of H, alkyl, phenyl, benzyl, —C(O)OH, —C(O)Oalkyl,—C(O)Ophenyl, —C(O)alkyl, —C(O)N H-phenyl, —C(O)NH-pyridyl,—C(O)NH-thiophenyl, OH, —O-alkyl, and —O-cycloalkyl.